Department of Dermatology, University of Regensburg, Regensburg, Germany.
J Invest Dermatol. 2013 Aug;133(8):1998-2003. doi: 10.1038/jid.2013.24. Epub 2013 Jan 21.
Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.
色素性角化病（PPK）是一种罕见的表皮痣综合征，其特征是皮脂腺痣和斑驳性色素痣同时存在。根据双斑假说，表皮痣和黑素细胞痣的共存可以用两种纯合隐性突变来解释，PPK 已成为人类的一个假定范例。然而，其潜在的基因突变仍然未知。我们使用 SNaPshot 分析和 Sanger 测序法分析了 6 名 PPK 患者的多种组织中 RAS、FGFR3、PIK3CA 和 BRAF 突变的存在情况。我们在 4 名患者中发现了杂合 HRAS c.37G>C（p.Gly13Arg）突变，在 2 名患者中发现了杂合 HRAS c.182A>G（p.Gln61Arg）突变。在每种情况下，突变均存在于皮脂腺痣和黑素细胞痣中。在后一种病变中，黑素细胞被鉴定为携带 HRAS 突变。对各种非病变组织的分析显示 HRAS 序列为野生型，符合嵌合体。我们的数据没有提供遗传证据来支持先前提出的双斑假说。相反，PPK 最好用多能祖细胞中的 HRAS 后激活突变来解释，该突变导致皮脂腺痣和黑素细胞痣同时发生。因此，PPK 是一种镶嵌性 RAS 病。
